Specific Genes Associated with Adverse Events of Methylphenidate Use in the Pediatric Population: A Systematic Literature Review

The aim of this study was to review empirical studies examining associations between candidate genes and adverse events (AEs) from methylphenidate (MPH) use in children and adolescents. The PubMed, EMBASE, CINAHL, and Web of Science databases were searched from their inception until March 2017. We included empirically based articles on pharmacogenetic studies in 0-17-year-old patients that investigated associations between specific candidate genes, their polymorphisms, and reported AEs. We extracted information about study design, setting, type of AE reporter, studied genes and their polymorphisms, age and gender, administered doses, method of genotyping, outcome measures, and main findings. A total of nine articles reporting information about four double-blind, placebo-controlled, cross-over studies and five open-label cohort studies were eligible for inclusion. Studies were published from 2006 onward and included a total of 998 patients (3-17-year-olds) diagnosed with attention-deficit hyperactivity disorder (ADHD). Studies predominantly involved males and lasted from 1 to 12 weeks. Studies used polymerase chain reaction and single nucleotide polymorphism genotyping methodology. Reported AEs were significantly associated with the following genes: appetite reduction (CES1*G); buccal-lingual movements (T1065G); diastolic blood pressure (ADRA2A Mspl C/C-GC); emotionality (DAT1*9/9); irritability (SNAP25 T1065G); picking (DRD4*7/DRD4*4); social withdrawal (DRD4*7/DRD4*4); somatic complaints (DAT1*10/10); tics (5-HTTLRP*S/L*L/L; SNAP25 T1065G); sadness (CES1*rsl12443580); and vegetative symptoms (5-HTTLPR). In conclusion, only few MPH pediatric pharmacogenetic studies were located, and large between-study heterogeneity was found. Studies were of naturalistic design and of short duration. They included small patient samples, poorly standardized treatment regimens, and limited outcome assessments. In the future, more pharmacogenomic studies in ADHD are needed, preferably using randomized, controlled study designs and of longer duration (more than 6 months).